HAL 2234-2242 pitz 9 th

The Porphyrias :: Eric W. Gou & Karl E. Anderson

INTRODUCTION Porphyrias are metabolic diseases caused by abnormalities of the 8 enzymes in
the heme biosynthetic pathway. All but one arise from mutation of a pathway enzyme; the
exception is porphyria cutanea tarda (PCT), which develops as an acquired deficiency of the
fifth enzyme in the pathway with or without a mutation. Porphyrias are classified as hepatic or
erythropoietic based on whether heme precursors first accumulate in liver or bone marrow, the
tissues that most actively synthesize heme. Porphyrias are categorized clinically based on their
clinical features as either cutaneous or acute (Table 124-1). Cutaneous porphyrias are due to
overproduction and accumulation of photosensitizing porphyrins. Most, as exemplified by PCT,
cause chronic blistering and scarring on sun-exposed areas of skin, whereas protoporphyrias
produce an acute, severe, and mostly nonblistering reaction to light, often leaving few if any
chronic skin changes. Acute porphyrias are characterized by neurologic symptoms and elevated
levels of the porphyrin precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG).
Porphyrins also accumulate in acute porphyrias, and sometimes achieve levels in plasma
sufficient to cause cutaneous blistering, as exemplified especially by variegate porphyria (VP). In
some porphyrias, damage to other organs, such as liver and kidney, may also occur. Symptoms,
signs, and histologic findings caused by porphyrias are nonspecific, whereas patterns of
porphyrins and porphyrin precursors enable specific diagnoses and treatments (Table 124-2).
HISTORICAL PERSPECTIVE
The first known description of porphyria was in 1874 by Schultz. He described a 33-year-old
man with photosensitivity since 3 months of age with associated anemia, splenomegaly, and
red urine.1,2 T. McCall Anderson in 1898 described 2 brothers with blistering of sun-exposed
skin, extensive scarring of facial features, and red urine.3 These patients are thought to have
had congenital erythropoietic porphyria (CEP), a very rare and severe cutaneous porphyria.
Acute porphyria was first described by Stokvis in 1888 in an elderly woman with symptoms
after taking sulphonal, a sedative related to barbiturates; she developed dark red urine and
later died.4 In 1923, Archibald Garrod proposed the term inborn errors of metabolism to
describe a number of inherited metabolic disorders, including the porphyrias.5
Porphyrias were first classified as hepatic or erythropoietic in 1954.6 Treatment of porphyria
cutanea tarda by phlebotomy was introduced by Ippen in 1961.7 In 1970, an inherited enzyme
deficiency was first described in acute intermittent porphyria,8 and hemin therapy was first
introduced for this condition in 1971.9 In the decades that followed, the enzymes of the
pathway and their genes were characterized and multiple mutations found in each of the
porphyrias. Also, regulation of heme synthesis especially in liver and bone marrow has become
better understood. Based on these advances, additional treatments have been introduced and
are being developed.
HEME SYNTHESIS AND FUNCTIONS
Heme, or iron protoporphyrin IX, is synthesized in eukaryotic cells in 8 steps, each catalyzed by
a different enzyme (Fig. 124-1). The first and last 3 of these enzymes are in the mitochondria
and the other 4 are cytosolic. The first enzyme, δ-aminolevulinic acid synthase (ALAS),
combines glycine and succinyl-coenzyme A to produce the amino acid δ-aminolevulinic acid
(ALA), also known as 5-aminolevulinic acid. Two molecules of ALA are then combined to form a
pyrrole, porphobilinogen (PBG). Four molecules of PBG are joined to form a linear tetrapyrrole,
hydroxymethylbilane (HMB). HMB is a substrate for the fourth enzyme, which inverts one of
the pyrrole rings of HMB and cyclizes the molecule to create uroporphyrinogen III, the first
porphyrin in the pathway. This asymmetric molecule undergoes a series of decarboxylations
and an oxidation to form protoporphyrin IX. Iron is then inserted to form heme. With the
exception of protoporphyrin IX, the porphyrin intermediates in this pathway are in their
reduced forms (ie, porphyrinogens).10 The end product heme consists of an iron atom in the
ferrous (reduced) state (Fe2+) bound to the 4 pyrrolic nitrogens of the porphyrin macrocycle
(Fig. 124-1), leaving 2 unoccupied electron pairs. Heme is the prosthetic group for many
essential hemoproteins. In hemoglobin, for example, one unoccupied electron pair is
coordinated with a histidine residue of the globin chain while the other is available to bind
molecular oxygen. Hemin is the chemical term for the oxidized form of heme, ferric
protoporphyrin IX, which has only one residual positive charge, and can be isolated from blood
and other tissues in the chloride form. Hemin also refers generically to biologics, namely,
lyophilized hematin (heme hydroxide) and heme arginate, which are available for treatment of
acute porphyrias. Approximately 85% of heme synthesis occurs in the bone marrow to support
hemoglobin formation, with the remainder mostly in the liver, primarily for cytochrome P450
enzymes (CYPs) found in the endoplasmic reticulum.11 All other tissues synthesize heme in
smaller amounts. Examples of the numerous other vital hemoproteins include myoglobin,
mitochondrial respiratory cytochromes, nitric oxide synthase, and catalase. Heme synthesis in
the liver is regulated primarily by the activity of δ-aminolevulinic acid synthase 1 (ALAS1, the
housekeeping form of ALAS, the first enzyme in the pathway), with repression of synthesis of
this enzyme and its import into mitochondria by heme, the end product of the pathway. In the
marrow, heme and globin synthesis are closely coordinated during erythropoietin signaling.
Expression of ALAS2, the erythroid-specific form of ALAS, and a number of other pathway
enzymes, are stimulated by heme or iron and by erythroid-specific cis-acting elements including
GATA-1 and NF-E2, culminating with phosphorylation of ferrochelatase (FECH), the final enzyme
in heme synthesis.12

PORPHYRIA CUTANEA TARDA

■ Characterized by skin friability and blistering lesions on sun-exposed areas of skin
■ Caused by inhibition of hepatic uroporphyrinogen decarboxylase (UROD) activity
■ This leads to excess amounts of highly carboxylated porphyrins in liver, plasma, urine, and
feces in diagnostic patterns
■ Genetic factors that predispose may include mutations of UROD (heterozygous, only in ∼20%
of cases) and hemochromatosis (HFE)
■ Acquired susceptibility factors (alcohol, smoking, secondary iron overload, chronic hepatitis C,
HIV, and estrogen) are often multiple
■ Responds readily to repeated phlebotomy while following serum ferritin, or low-dose
hydroxychloroquine

PCT is the most common porphyria, and is characterized by the development of skin friability
and chronic, blistering lesions on the dorsal aspects of the hands and other sun-exposed areas
of skin usually in mid- or late life.13 The underlying cause is deficient uroporphyrinogen
deaminase (UROD) activity in hepatocytes, where uroporphyrinogen and other highly
carboxylated porphyrinogens accumulate and are oxidized to the corresponding porphyrins. In
active cases, hepatic UROD activity is reduced to less than ∼20% of normal. PCT is an iron-
related disorder and develops only in the presence of normal or increased amounts of hepatic
iron. Multiple susceptibility factors contribute to iron accumulation, oxidative stress, and
generation of a UROD inhibitor in hepatocytes, and are important to identify in individual
patients. This is the only porphyria that can develop in absence of the mutation of the affected
enzyme.14 Heterozygous UROD mutations are found in ∼20% of patients, but these do not
cause PCT in the absence of other susceptibility factors. PCT is the most readily treated
porphyria, responding well to either phlebotomy or low-dose hydroxychloroquine. But the
disease must first be differentiated from other less common porphyrias that cause identical skin
lesions but are unresponsive to these treatments.
CLINICAL FEATURES
PCT usually develops in the fourth or fifth decade of life, most commonly in males. Fluid-filled
blisters and bullae are found especially on the dorsal hands (Fig. 124-2), the most sun-exposed
areas of the body, and often arise after minor or inapparent trauma as a result of increased skin
friability. Blisters may also occur on the forearms, face, ears, neck, legs, and feet. These rupture
easily, leaving erosions that may become dry and crusted and heal slowly (Fig. 124-2). Eroded
areas of skin are prone to bacterial infection. Residual scarring and hyper- and
hypopigmentation are prominent with prolonged disease. Milia may precede or follow vesicle
formation. Facial hypertrichosis and hyperpigmentation (Fig. 124-3) are common, may even
occur in the absence of blistering, and are cosmetically problematic, especially in women.16
Severe thickening of affected areas of skin, sometimes with associated calcification, can
resemble systemic sclerosis and is termed pseudoscleroderma. Neurologic symptoms
characteristic of the acute porphyrias are not seen in PCT. Rare childhood cases have often
been associated with UROD mutations and cancer chemotherapy15 (Fig. 124-3). The disease
may develop during pregnancy, possibly related to effects of increased estrogen. Reported
associations with cutaneous and systemic lupus erythematosus are unexplained. PCT associated
with end-stage renal disease is usually more severe, because urinary excretion of porphyrins is
impaired, and porphyrins are poorly dialyzed. The resulting plasma porphyrin levels can equal
those seen in congenital erythropoietic porphyria (CEP) and be associated with severe bacterial
infections and mutilation.17
Mild abnormalities in liver function tests are found in almost all cases. Fresh hepatic tissue
exhibits strong red fluorescence on exposure to long-wave ultraviolet light (Fig. 124-4),
reflecting massive accumulation of porphyrins. Liver histopathology is nonspecific and usually
includes increased iron, increased fat, hepatocyte necrosis and inflammation, which in many
cases reflects the effects of alcohol or hepatitis C infection. Cirrhosis is unusual at the onset of
PCT. The risk of HCC is increased, especially with more prolonged disease, perhaps due partly to
concomitant susceptibility factors that themselves can cause chronic liver damage and
fibrosis.18-20
SUSCEPTIBILITY FACTORS
PCT is a multifactorial disorder, with many common susceptibility factors contributing to the
disease, none of which is present in every patient. These include genetic factors, viral
infections, and chemical exposures. Patients almost always possess multiple such factors, which
have other health implications.21 For example, in a large series of 143 patients with PCT in the
United States, the most common susceptibility factors were ethanol use (87%), smoking (81%),
chronic hepatitis C (69%), and HFE (hemochromatosis) mutations (53%).22 These factors are
common in the general population but do not by themselves cause PCT to develop. Additional
susceptibility factors are likely to be identified in the future.
UROD MUTATIONS Most PCT patients do not have a UROD mutation and are said to have
sporadic (type 1) disease. Approximately 20% of patients have a heterozygous predisposing
UROD mutation and are labeled as familial (type 2) PCT. Such mutations are inherited as
autosomal
dominant traits, but with low penetrance, so most type 2 patients present sporadically, having
no known relatives with PCT. Having such a mutation is a susceptibility factor that does not
cause PCT in the absence of other acquired or inherited susceptibility factors. HEP is the
homozygous form of type 2 PCT, and resembles CEP clinically. At least 100 different mutations
of the UROD gene, mostly missense mutations occurring in 1
or a few families, have been identified in type 2 PCT and HEP (Table 124-1). Type 3 refers to
rare families with more than 1 affected individuals but no UROD mutation. All 3 PCT types are
clinically identical, although disease onset is sometimes earlier in type 2.23
IRON AND HEMOCHROMATOSIS GENE (HFE) MUTATIONS Iron stores are always normal or
increased in PCT, whereas iron deficiency is protective. Iron provides an oxidative environment
in hepatocytes and facilitates generation of a UROD inhibitor, but does not itself directly inhibit
UROD. The C282Y mutation of the HFE gene, the major mutation causing hemochromatosis in
whites, is more prevalent in both sporadic and familial PCT than in unaffected individuals. Up to
10% to 20% of patients may be C282Y homozygotes, and these may experience earlier onset of
disease.23,24 In southern Europe, where the C282Y is less prevalent, the H63D mutation is
more commonly associated with PCT.25 HFE mutations impair sensing of serum iron, thereby
reducing hepatic hepcidin production. Because circulating levels of hepcidin are inappropriately
low, downregulation of enterocyte ferroportin by hepcidin is impaired, leading to
inappropriately high intestinal iron absorption. Hepatic hepcidin expression is also reduced in
PCT patients without HFE mutations, because some other susceptibility factors reduce
expression of this hormone, as noted below.26
ALCOHOL PCT has long been associated with alcohol abuse. Alcohol and its metabolites may
predispose to onset of PCT by inducing hepatic ALAS1 and CYPs, generating reactive oxygen
species, and causing mitochondrial injury, lipid deposition, depletion of reduced glutathione
and other antioxidant defenses, increasing production of endotoxin and activating Küpffer cells.
Alcohol intake can also reduce hepcidin expression.26
SMOKING AND CYTOCHROME P450 ENZYMES Smoking is frequently associated with alcohol use
but is regarded as an independent risk factor in PCT.21 Smoking may increase oxidative stress in
hepatocytes and induces hepatic CYPs, including CYP1A2 which is important for development of
uroporphyria in rodent models of PCT.27,28 Hepatic CYPs are often increased in human PCT,29
but it is unclear which CYPs contribute to the disease. However, a more inducible CYP1A2
variant was found to be more common in PCT than in normal subjects.30,31
ESTROGENS Estrogen use is common in women with PCT.21,32,33 The disease has also
occurred in some men treated with estrogen for prostate cancer.32 Female rats or males
receiving estrogens are more susceptible to development of chemically-induced uroporphyria
than untreated males.34 The mechanism for this predisposition is not certain, but may be
secondary to generation of reactive oxygen species.14,35
HEPATITIS C Hepatitis C promotes hepatocyte steatosis, iron accumulation, mitochondrial
dysfunction, oxidative stress and dysregulation of hepcidin expression.36,37 The prevalence of
chronic hepatitis C in PCT ranges from 21% to 92% in various countries, and always exceeds the
prevalence of this viral infection in the general population. Only an estimated 0.05% of
individuals with chronic hepatitis C develop PCT.38 Large differences in the prevalence of this
viral infection in PCT in different countries reflects the considerable geographic variation in
prevalence of this infection in atrisk populations.
HIV PCT is less commonly associated with HIV infection, which may be present with or without
HCV coinfection.39 PCT can be the initial manifestation of HIV infection. The mechanism for the
association with HIV infection and possible relationships to specific antiretroviral therapies are
not established.
ANTIOXIDANTS Reduced plasma levels of ascorbate and carotenoids have been noted in some
patients with PCT.40-42 Rodents with ascorbate deficiency are more susceptible to
development of uroporphyria.43
CHEMICAL EXPOSURE AND DRUGS A large outbreak of PCT occurred in eastern Turkey in the
1950s during a period of food shortage when the population consumed seed wheat treated
with the fungicide hexachlorobenzene.44 Smaller outbreaks and individual cases of the disease
have occurred after exposures to other chemicals such as 2,3,7,8tetrachlorodibenzo-p-dioxin
(TCDD, dioxin).45 These and related chemicals cause biochemical features of PCT in laboratory
animals and cultured hepatocytes.10,14
ETIOLOGY AND PATHOGENESIS
PCT develops when hepatic UROD activity is reduced to ∼20% of normal.14 With enzyme
inhibition, the amount of UROD protein remains at its genetically determined level in the
liver.46,47 As previously discussed, about 20% of patients are heterozygous for UROD
mutations and are more susceptible to developing PCT, because their UROD activity in the liver
(as well as other tissues) is half-normal from birth. PCT does not manifest in these individuals
unless further reduction of UROD activity occurs in the liver. A UROD inhibitor, characterized as
a uroporphomethene, was identified in a mouse model that spontaneously develops
biochemical features of PCT. This inhibitor is a product of partial oxidation of
uroporphyrinogen, possibly generated by 1 or more CYPs (Fig. 124-5).49 UROD sequentially
decarboxylates uroporphyrinogen I and III (each with 8 carboxyl side groups) to
coproporphyrinogen I and III (each with 4 carboxyl
groups), respectively. Both isomers are substrates for UROD, but uroporphyrinogen III is
preferred. (The next enzyme in the pathway is specific for coproporphyrinogen III as a
substrate, so uroporphyrinogen I and coproporphyrin I are not heme precursors.) When hepatic
UROD is inhibited, uroporphyrinogen I and III and the intermediates in the reaction (ie, I and III
isomers of hepta-, hexa-, and pentacarboxyl porphyrinogen) accumulate as the corresponding
oxidized porphyrins, and are eventually transported in plasma to the skin, causing
photosensitivity, and to the kidneys for excretion. Biliary and fecal porphyrins are also
increased. Porphyrins in their oxidized state are reddish, fluorescent, and photosensitizing,
whereas porphyrinogens do not have these properties. The polycyclic aromatic structure of
oxidized porphyrins contains delocalized electrons, which increase in energy level on exposure
to violet light (at a wavelength of ∼410 nm). This energy may be released at a higher
wavelength as red fluorescent light or transferred to molecular oxygen, forming reactive singlet
state oxygen and other reactive oxygen species. These may damage cutaneous cellular
constituents or cause mast cell degranulation and complement activation.50,51 Damage to the
subepidermal layers of skin makes the skin friable and prone to blistering.50,51
DIAGNOSIS
PCT develops most commonly in adult males in association with factors such as excess alcohol
use, smoking and chronic hepatitis C, and in females, particularly with estrogen use. The
presentation is usually characteristic, but it must be remembered that adults with variegate
porphyria (VP), hereditary coproporphyria (HCP) or pseudoporphyria, and children or adults
with congenital erythropoietic porphyria (CEP) or hepatoerythropoietic porphyria (HEP) can
present with identical skin lesions. Therefore, it is essential to establish a laboratory diagnosis
of PCT before initiating treatment. First-line testing (ie, screening) for PCT is measurement of
total plasma or urine porphyrins. Normal results may indicate a diagnosis of pseudoporphyria.
Because elevated porphyrins, especially in urine, is common in liver disease and other medical
conditions, a finding of increased porphyrins and does not itself support a diagnosis of
porphyria. Therefore, if firstline testing is positive, the following are suggested to establish a
diagnosis and exclude other less common porphyrias that can cause similar skin manifestations
and often be misdiagnosed as PCT:
■ Fluorescence scanning of diluted plasma at neutral pH.52 The porphyria most commonly
misdiagnosed as PCT is VP,53 and is rapidly and reliably recognized by plasma scanning and
finding an emission peak at ∼626 nm, in contrast to ∼620 nm for PCT and other blistering
cutaneous porphyrias.
■ Fractionation of urine or plasma porphyrins, which will show a predominance of
uroporphyrin, and hepta-, hexa-, and pentacarboxyl, porphyrins in PCT. This pattern of
predominance of highly carboxylated porphyrins is not fully diagnostic, as it can occur in other
much less common porphyrias that can be misdiagnosed as PCT especially when they present in
adults.
■ Total erythrocyte porphyrins, which are normal or modestly elevated in PCT, but markedly
elevated in rare cases of CEP, HEP, or homozygous HCP or VP. These usually present in infancy,
but can first become manifest in adults, sometimes in associated with a clonal
myeloproliferative or myelodysplastic disorder.
■ Fecal porphyrins may be normal or modestly increased in PCT, with a complex pattern that
includes isocoproporphyrins. These atypical tetracarboxylporphyrins are formed when
pentacarboxylporphyrinogen accumulates in liver as a result of UROD inhibition and undergoes
premature decarboxylation by CPOX, the next enzyme in the pathway, forming
dehydroisocoproporphyrinogen. The latter is excreted in bile and undergoes oxidation by
intestinal bacteria to isocoproporphyrins.54 In contrast to PCT, fecal porphyrins are markedly
elevated in CEP, HCP, and VP, with a predominance of coproporphyrin I in CEP, coproporphyrin
III in HCP, and both coproporphyrin III and protoporphyrin in VP.
■ Urine ALA is normal or modestly increased in PCT, and PBG is always normal. Levels of these
porphyrin precursors may be elevated in the acute hepatic porphyrias, AIP, HCP and VP. An
increase of plasma porphyrins and demonstration of a predominance of highly carboxylated
porphyrins is essential for diagnosis of PCT in patients with advanced renal disease, although
the reference range is higher in this population.55 Advanced renal disease is commonly
associated with altered erythropoiesis and resulting increases in erythrocyte zinc
protoporphyrin, which should not be attributed to PCT or other porphyria. Patients with AIP
and end-stage renal disease sometimes present with blistering skin lesions that resemble
PCT.56 Although not required for diagnosis of PCT, skin biopsy reveals characteristic but
nonspecific findings such as subepidermal blistering and deposition of periodic acid–Schiff-
positive material around blood vessels and fine fibrillar material in the upper dermis and at the
dermoepithelial junction. Deposits of immunoglobulins and complement are also found.57
These histologic changes are also seen in other cutaneous porphyrias as well as
pseudoporphyria, a poorly understood condition that presents with lesions that closely
resemble PCT, but with plasma porphyrins that are not significantly increased.58
IDENTIFICATION OF SUSCEPTIBILITY FACTORS
All PCT patients should be questioned or examined for the following susceptibility factors, some
of which are modifiable: alcohol and estrogen use, smoking, hepatitis C and HIV infection, and
HFE and UROD mutations. Use of drugs that exacerbate acute porphyrias are seldom implicated
in PCT. Although familial (type 2) cases of PCT can be identified by half-normal erythrocyte
UROD activity, UROD mutation analysis is more dependable. This full analysis of susceptibility
factors helps explain the disease in individual cases and may affect management. Moreover,
some of these factors also have medical implications of their own. Serum ferritin should be
measured and may influence choice of treatment.
THERAPY
Treatment with phlebotomy or low-dose hydroxychloroquine is highly effective in both sporadic
and familial forms of PCT. These should be initiated only after the diagnosis is certain, because
they are not effective in other porphyrias. It may be reasonable to start treatment after plasma
porphyrin results, including fluorescence scanning,52 are consistent with PCT and have
excluded VP and pseudoporphyria. Patients should be advised to stop smoking and alcohol
consumption. Use of estrogen and drugs known to induce hepatic heme synthesis should be
discontinued if possible. Estrogen replacement therapy, preferably transdermal, can be
considered, if needed, after PCT is in remission.59 Adequate intake of ascorbic acid and other
nutrients should be established. Removal of 1 or more susceptibility factors can lead to
improvement, but the response is slow or unpredictable.60 Repeated phlebotomy to reduce
hepatic iron is the preferred treatment at most institutions. Removal of 450 mL blood at 2-week
intervals is guided by the serum ferritin level, with a target of 15 to 20 ng/mL (ie, near the lower
limit of normal). Measurement of hematocrit and ferritin at each session allows monitoring to
prevent symptomatic anemia and assess progress toward the target ferritin level. Phlebotomies
are stopped when the ferritin from the previous visit is 25 to 30 ng/L, and ferritin is measured
to confirm that the target level was reached. At that point, porphyrin levels may not have
become completely normal and skin lesions are not completely resolved. Additional iron
depletion is not beneficial and leads to anemia. Most patients require 6 to 8 phlebotomies for
biochemical and clinical remission, but additional sessions may be necessary, especially if the
baseline serum ferritin level is markedly elevated. Decreases in plasma (or serum) porphyrin
levels tend to lag behind serum ferritin, but will normalize within weeks after phlebotomies are
completed.61,62 Friability of skin may persist for some time after porphyrin levels are normal,
until healing and repair of the subepidermal layer of the skin is complete. Subsequent
phlebotomies are generally not needed, with the exception of patients homozygous or
compound heterozygous for the C282Y HFE mutation, as current guidelines for
hemochromatosis recommend maintaining a ferritin level between 50 and 100 ng/mL.63
Relapse of PCT may occur, often related to resumption of alcohol use, but usually responds to
retreatment. Following porphyrin levels after remission can detect recurrences early so that
retreatment can be reinstituted promptly. A low-dose regimen of hydroxychloroquine (or
chloroquine) is an effective alternative to phlebotomies, and is the preferred approach at some
institutions.14,64-70 These 4-aminoquinoline antimalarials do not appear to deplete hepatic
iron, but mobilize porphyrins that have accumulated in lysosomes and other intracellular
organelles in hepatocytes. Full therapeutic doses of these drugs rapidly mobilize porphyrins and
induce an acute hepatitis, characterized by fever, malaise, nausea, and marked increases in
urinary and plasma porphyrins and photosensitivity, but followed by remission.71 Unmasking of
previously unrecognized PCT with use of chloroquine for malaria prophylaxis has been
described.72 A low-dose regimen (hydroxychloroquine 100 mg or chloroquine 125 mg [one half
of a standard tablet] twice weekly) is recommended to achieve remission and avoid the side
effects of full doses of these drugs.64,67,68 Treatment is continued until plasma or urine
porphyrins are normalized for at least a month. Patients who respond poorly may require
alternate therapy with phlebotomy.71 These medications are associated with a small risk of
retinopathy,73 which may be lower with hydroxychloroquine. Therefore, patients should be
screened by an ophthalmologist before treatment.74 Comparison of treatment with
phlebotomy or hydroxychloroquine (100 mg twice weekly), showed that time to remission
(normal plasma porphyrin levels) was comparable with these treatments.70 Treatment with an
iron chelator such as desferrioxamine is much less efficient for removal of iron than
phlebotomy, but can be considered if both phlebotomy and low-dose hydroxychloroquine are
contraindicated.75 Treatment of hepatitis C with interferon-based regimens is lengthy and
often not successful. Therefore we have first treated PCT, which is usually more symptomatic,
and after achieving remission, then treated coexisting hepatitis C. Interferon-based treatment
regimens commonly cause anemia, which usually precludes phlebotomy for PCT, and are
sometimes associated with relapse of previously treated PCT.76 Experience with low-dose
hydroxychloroquine during concurrent treatment of hepatitis C is limited. The new direct-acting
antivirals can treat this infection rapidly and dependably, and studies are under way to collect
evidence whether they should be used instead of phlebotomy or low-dose hydroxychloroquine
as initial treatment of PCT associated with hepatitis C.76 PCT associated with end-stage renal
disease is often difficult to treat. Phlebotomy is effective if supported, as needed, by starting or
increasing the dose of erythropoietin.17,77,78 High-flux hemodialysis may provide some
benefit.79 Renal transplantation can lead to remission presumably because of resumption of
endogenous erythropoietin production and reduced hepcidin levels.80 Periodic screening for
hepatocellular carcinoma should include liver imaging by abdominal ultrasonography or
computed tomography. As in other liver diseases, this should be guided by evidence of cirrhosis
or hepatic fibrosis, which may be assessed by liver biopsy or indirectly by elastography, and the
presence of other causes of liver disease.

RENAL SYSTEM ( pitz 9th hal 2436-2440)

Patients with end-stage renal disease (ESRD) develop a variety of cutaneous findings related to
metabolic abnormalities, including anemia, calcium-phosphate dysregulation, and glucose
intolerance. Skin manifestations include a sallow appearance, pruritus, xerosis, acquired
perforating dermatosis, pseudoporphyria, calciphylaxis, and uremic frost. The skin can be pale
as a consequence of anemia and often exhibits a distinctive muddy hue, partly from
accumulation of carotenoid and nitrogenous pigments (urochromes) in the dermis.30 Uremic
frost results from eccrine deposition of urea crystals on the skin surface of individuals with
severe uremia.
RENAL PRURITUS
Renal pruritus is a major problem and may be seen in as many as 90% of those undergoing
hemodialysis.31-33 The etiology is thought to be multifactorial, including xerosis, peripheral
neuropathy, mast cell hyperplasia, and increased serum histamine, vitamin A, parathyroid
hormone, and inflammatory factors.34-36 Clinically, the skin may appear normal or
demonstrate secondary changes such as lichenification, excoriation, and hyperpigmentation.
NAIL CHANGES
Lindsay nails (half-and-half nails) are seen frequently in patients on dialysis and resolve with
renal transplantation. They are characterized by a dull-white color proximally and a
nonblanching red, pink, or brown color distally. Other abnormalities include Beau lines,
onycholysis, and nailfold capillary abnormalities.
SPECIFIC CONDITIONS
Table 133-6 outlines select conditions with renal and cutaneous manifestations.

CALCIPHYLAXIS
Metastatic calcification in ESRD results from dysfunction of calcium and phosphate
homeostasis. Calcification of vessels is common in ESRD and is seldom symptomatic.
Occasionally, however, deposition of calcium phosphate in the media of cutaneous vessels
results in downstream ischemia and infarct known as calciphylaxis. Painful violaceous mottling
and fixed livedo reticularis progress to firm plaques of retiform purpura, followed by black
eschar, and ulceration. Mortality is high—roughly 50% at 1 year—most often from sepsis.
Parathyroid hormone is usually elevated, while the calcium-phosphate product is often normal
when checked. Treatment of calciphylaxis is multimodal and includes sodium thiosulfate, low
calcium bath dialysis, non–calcium phosphate binders, bisphosphonates, calcimimetics,
debridement of necrotic tissue, and aggressive wound care.
BULLOUS DISEASES OF HEMODIALYSIS
Porphyria cutanea tarda may occur in patients with ESRD on dialysis. Although the etiology of
this phenomenon is unclear, inadequate clearance of plasma-bound porphyrins by the kidneys
or hemodialysis may lead to porphyrin deposition in the skin, with resulting skin fragility and
blister formation in sun-exposed areas.37,38 Patients on hemodialysis may also produce or be
exposed to compounds that alter normal heme synthesis. Bullous dermatosis of dialysis or
pseudoporphyria may occur in up to one-fifth of patients on hemodialysis. This condition is
often clinically indistinguishable from porphyria cutanea tarda. Hypertrichosis is less common,
and plasma porphyrin levels are typically normal. When treating porphyria cutanea tarda or
pseudoporphyria, phlebotomy can reduce iron levels in the liver, allowing new hepatic
uroporphyrinogen decarboxylase to be formed.39 However, patients with ESRD often have
significant anemia and cannot tolerate phlebotomy. Erythropoietin may both lower total body
iron stores and support phlebotomy as needed.40,41 Lowdose hydroxychloroquine or
chloroquine effectively clear porphyrins from the liver, but these may not be eliminated in the
setting of poor renal function. Deferoxamine may lower serum porphyrin levels in some
patients. Renal transplantation is an option in refractory disease.42
ACQUIRED PERFORATING DERMATOSES (KYRLE DISEASE)
Acquired perforating dermatoses are a spectrum of disorders associated with ESRD and
diabetes that involve transepidermal elimination of collagen or elastic fibers. They occur in up
to 10% of patients undergoing hemodialysis.43 Clinically, patients develop hyperkeratotic
papules or nodules with a central crustfilled plug on the trunk and extensor surfaces, often in a
linear distribution. Proposed mechanisms include diabetic microangiopathy, dysregulation of
vitamin A or vitamin D metabolism, abnormality of collagen or elastic fibers, and inflammation
and connective tissue degradation by dermal deposition of substances such as uric acid and
calcium pyrophosphate.44 Many authorities regard this entity as a response to trauma caused
by scratching in chronic renal pruritus. Successful treatment depends on addressing the
underlying etiology of pruritus. Topical and intralesional glucocorticoids, topical and systemic
retinoids, cryotherapy, and ultraviolet light may be useful.